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Imagine a plate filled with vegetables, vibrant with color. They're sprinkled with nuts, drizzled with extra-virgin olive oil, and topped with a tidy serving of grilled salmon or, perhaps, tofu. Sliced strawberries decorate the plate's edge. Now imagine scraping away a sizable wedge—as much as a third—of that meal. Even worse, imagine this subtraction occurring day in and day out, whisking away food and nearly half the calories of each meal.

Such spare servings aren't simply a formula for weight loss. They're part of a considered lifestyle based on the idea that a lean life might lead to a longer life marked by fewer age-related diseases and slowed senescence. On the edge of starvation, deep in the heart of hunger, some believe they have found the fountain of youth.

A Slim Edge

The roots of this belief can be traced to evolutionary changes incorporated billions of years ago into the genes of living organisms. When severely stressed, as when an organism is hungry almost to the point of starvation, running repeatedly from unrelenting predators, or chasing ever-elusive prey, cells within the body open chemical pathways that increase the efficiency of energy processing and speed up the repair and recycling of damaged proteins, allowing the organism to survive. In humans, these responses improved our chances for survival throughout the millennia. But scientists think stress responses may have another role: they may help prevent cancer, diabetes, and other diseases associated with aging.

"Since the ancient Greeks, we've known that exercising and eating less or fasting is good for you, but we've never really known why," says David Sinclair, an HMS professor of genetics and a codirector of the Paul F. Glenn Laboratories for the Biological Mechanisms of Aging at Harvard Medical School.

Sinclair studies sirtuins, a family of genes found in most living things. He thinks these genes may play key roles in the stress-related responses that protect us against disease and increase our chances for living longer and remaining healthy. In addition, Sinclair and other scientists think that therapeutics based on sirtuins or their activity may help trigger the genes and biochemical pathways that control the effectiveness of our disease defenses, which may become less active as we age.

Less Is More

Currently, the best understood means of triggering a cascade of anti-aging defenses is calorie restriction. Research has shown it plays a crucial role in preventing obesity, fighting diabetes, preventing tumor growth, and metabolizing fat. There's also evidence that, while calorically restricted animals become infertile while they are hungry, once they start to eat again they can delay menopause and extend fertility much later into life than normal.

The first experiments on calorie restriction, which took place during the Great Depression, were conducted on rats. Researchers cut back the amount of food they gave to the animals and expected to see the animals' health deteriorate. Instead, the rats' health improved and they lived longer. In just about every creature in which calorie restriction has been tested—brewer's yeast, bacteria, roundworms, and mice—it has lengthened the life span of the species, sometimes nearly doubling it. What's more, vitality remained high even as age increased.

SLOW BURN: Some tortoise species live 150 years or more.

Humans already have a long life span. In fact, only a few species of animals outlive us: Some tortoises live to be 150 or so, and bowhead whales may reach 200. Certain plant species, like the bristlecone pine, live thousands of years in the austere environments of the arid southwestern United States. Interestingly, the bristlecone and similar long-lived plants might be said to practice a botanical version of calorie restriction.

Our long life span makes it difficult to measure the outcomes of calorie restriction. But one attempt, a short-term test, is found in research undertaken during World War II. A group of conscientious objectors volunteered to adhere to a diet that approximated the levels of deprivation found in the war-devastated regions of Europe. Scientists found that the participants not only experienced ravenous hunger, but that they were also constantly irritable. More troubling were the instances of participants suffering severe psychological troubles, including self-mutilation. One participant attempted suicide.

A contemporary, nonscientific look at the long-term effects of calorie restriction can be found among the thousands of members of the Calorie Restriction Society, based in New York. Society members voluntarily restrict their calorie intake by at least 25 percent of what might be considered normal for a healthy adult. They do this out of a conviction that by radically lowering their caloric intake, they will prolong their lives and stay healthy into their old age. Many adherents have steadfastly practiced their lean eating regimen for more than a decade.

Unfortunately, many people find it almost unimaginably hard to maintain this sort of diet. To achieve it, a moderately active 155-pound male would need to cut his intake from around 2,500 calories a day to around 1,800 calories, the caloric intake recommended for a low-activity male weighing less than 130 pounds. And cutting back to such spartan amounts is not the only challenge; in order to maintain healthy levels of key nutrients, the calories must be well chosen. That leaves precious little room for French fries or even low-fat French vanilla yogurt.

Round Round Get Around

T. Keith Blackwell

For those who despair that they haven't the will power to follow such a lean diet, yet still would like to enjoy a long, healthy life, there is good news. According to ongoing longitudinal studies of centenarians, most people who live extraordinarily long lives don't follow calorie restriction. They also often don't work out, or do anything else intended to prolong their lives.

Some early theories of aging posited that we grew old as we consumed our lifetime allotments of physiological actions—a quantum of calories to metabolize, a quantity of breaths, or a quota of heartbeats, for example. It was initially thought that calorie restriction worked because it slowed the body's clock and its inevitable ticking toward the end of life. It turns out that it's not the act of eating or processing fewer calories that matters. People who eat what they like, skip exercise, enjoy life, and still remain active for more than 100 years may simply have more robust repair processes than most of their peers.

These carefree super-centenarians give T. Keith Blackwell, an HMS professor of genetics at the Joslin Diabetes Center, hope for the field of aging research. "People who live past about 104 tend to be surprisingly healthy. Until they get a serious infection or the body just stops working, most of these super-centenarians are up and around and energetic," he says.

One goal for researchers who study aging, Blackwell says, would be to find a much simpler way to achieve a vital, disease-free old age than by calorie restriction—perhaps a drug, a particular pattern of exercise, or tweaking certain nutrients in the diet.

STRESS TESTERS: Researchers such as T. Keith Blackwell and David Sinclair (above) investigate how calorie restriction and other physiological pressures might prevent diseases that are associated with aging. In just about every creature in which calorie restriction has been tested—brewer’s yeast, bacteria, roundworms, and mice—it has lengthened the life span of the species, sometimes nearly doubling it.

To find that simpler way, Blackwell has been researching skn-1, a gene-regulating protein found in the much-studied roundworm Caenorhabditis elegans. This regulator is analogous to regulatory proteins coded for in the human genome. Skn-1 plays multiple roles in the life of a roundworm: It helps build its digestive system; it manages the recycling of wastes and toxins that contribute to its aging, and it triggers several of the roundworm's longevity pathways.

Blackwell has found that skn-1 is important to C. elegans in a variety of stress situations, not only when the organism undergoes calorie restriction. "Stress defenders talk to other stress defenders and help each other out," he says. It seems that there are many different stress-response processes and that they work together, back each other up, trigger, and reinforce one another in rather complicated ways.

But how do we get these processes talking to one another when we need them most? How do we make it so that we all can benefit from these life-prolonging powers?

"The complexity of this process at the nano scale is mind-blowing," Sinclair says. "And the challenge is to try to find a medicine that can directly tweak that system without causing any side effects at the nano level. It is going to take the careers of many people to get there."

Jake Miller is a writer and editor in the HMS Office of Communications and External Relations.